{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T06:18:59Z","timestamp":1783491539526,"version":"3.55.0"},"reference-count":314,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer\u2019s disease (AD), thus addressing long-standing translational obstacles posed by the disease\u2019s complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-region-specific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including A\u03b2 plaques, tau tangles, neuroinflammation, and blood\u2013brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype\u2013phenotype relationships for major AD genes (\n                    <jats:italic>APP<\/jats:italic>\n                    ,\n                    <jats:italic>PSEN1<\/jats:italic>\n                    ,\n                    <jats:italic>PSEN2<\/jats:italic>\n                    , and\n                    <jats:italic>APOE\u03b54<\/jats:italic>\n                    ), enable the dissection of signaling pathway dysregulation (Wnt\/\u03b2-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific \u201cavatar\u201d models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks\u2014including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization\u2014limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1791272","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:58:23Z","timestamp":1783490303000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling Alzheimer\u2019s disease with brain organoids: mechanisms, applications, and future directions"],"prefix":"10.3389","volume":"14","author":[{"given":"Qing","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Neurology, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]},{"name":"Engineering Laboratory of Memory and Cognitive Impairment Disease of Jilin Province, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]},{"name":"Engineering Laboratory of Memory and Cognitive Impairment Disease of Jilin Province, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxiu","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Neurology, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]},{"name":"Engineering Laboratory of Memory and Cognitive Impairment Disease of Jilin Province, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Kong","sequence":"additional","affiliation":[{"name":"Engineering Laboratory of Memory and Cognitive Impairment Disease of Jilin Province, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]},{"name":"Department of Vascular Surgery, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Liu","sequence":"additional","affiliation":[{"name":"Engineering Laboratory of Memory and Cognitive Impairment Disease of Jilin Province, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]},{"name":"Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1002\/bit.27606","article-title":"Extracellular vesicles from organoids and 3D culture systems","volume":"118","author":"Abdollahi","year":"2021","journal-title":"Biotech and Bioeng."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1007\/s40265-025-02250-5","article-title":"Clinical efficacy, safety and imaging effects of oral valiltramiprosate in APOE\u03b54\/\u03b54 homozygotes with early alzheimer\u2019s disease: results of the phase III, randomized, double-blind, placebo-controlled, 78-Week APOLLOE4 trial","volume":"85","author":"Abushakra","year":"2025","journal-title":"Drugs"},{"key":"B3","doi-asserted-by":"publisher","first-page":"47","DOI":"10.3390\/jox15020047","article-title":"Associations of environmental exposure to arsenic, manganese, lead, and cadmium with alzheimer\u2019s disease: a review of recent evidence from mechanistic studies","volume":"15","author":"Ahmed","year":"2025","journal-title":"JoX"},{"key":"B4","doi-asserted-by":"publisher","first-page":"102832","DOI":"10.1016\/j.arr.2025.102832","article-title":"Apheresis for senescence: targeting the senescence-associated secretory phenotype to delay aging and age-related diseases","volume":"111","author":"Akgun","year":"2025","journal-title":"Ageing Res. 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